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1.  New Rapid Diagnostic Tests for Neisseria meningitidis Serogroups A, W135, C, and Y 
PLoS Medicine  2006;3(9):e337.
Outbreaks of meningococcal meningitis (meningitis caused by Neisseria meningitidis) are a major public health concern in the African “meningitis belt,” which includes 21 countries from Senegal to Ethiopia. Of the several species that can cause meningitis, N. meningitidis is the most important cause of epidemics in this region. In choosing the appropriate vaccine, accurate N. meningitidis serogroup determination is key. To this end, we developed and evaluated two duplex rapid diagnostic tests (RDTs) for detecting N. meningitidis polysaccharide (PS) antigens of several important serogroups.
Methods and Findings
Mouse monoclonal IgG antibodies against N. meningitidis PS A, W135/Y, Y, and C were used to develop two immunochromatography duplex RDTs, RDT1 (to detect serogroups A and W135/Y) and RDT2 (to detect serogroups C and Y). Standards for Reporting of Diagnostic Accuracy criteria were used to determine diagnostic accuracy of RDTs on reference strains and cerebrospinal fluid (CSF) samples using culture and PCR, respectively, as reference tests. The cutoffs were 105 cfu/ml for reference strains and 1 ng/ml for PS. Sensitivities and specificities were 100% for reference strains, and 93.8%–100% for CSF serogroups A, W135, and Y in CSF. For CSF serogroup A, the positive and negative likelihood ratios (± 95% confidence intervals [CIs]) were 31.867 (16.1–63.1) and 0.065 (0.04–0.104), respectively, and the diagnostic odds ratio (± 95% CI) was 492.9 (207.2–1,172.5). For CSF serogroups W135 and Y, the positive likelihood ratio was 159.6 (51.7–493.3) Both RDTs were equally reliable at 25 °C and 45 °C.
These RDTs are important new bedside diagnostic tools for surveillance of meningococcus serogroups A and W135, the two serogroups that are responsible for major epidemics in Africa.
There are several strains ofNeisseria meningitidis that can cause seasonal outbreaks of meningitis in Africa. Treatment of patients and containment of the epidemic through vaccination depends on which strain is responsible. The new dipstick tests described here are accurate and suitable for storage and use in resource-poor settings.
Editors' Summary
Bacterial meningitis, a potentially deadly infection of tissues that line the brain and spinal cord, affects over 1 million people each year. Patients with bacterial meningitis usually have fever, headache, and stiff neck, and may become unconscious and die if the disease is not treated within hours. Most cases of bacterial meningitis occur in Africa, particularly in the arid savannah region south of the Sahara known as the Sahel, where epidemic outbreaks of meningitis occur periodically. This region, also called the “meningitis belt,” extends from Senegal and adjacent coastal countries in West Africa across the continent to Ethiopia. Although most outbreaks tend to occur in the dry season, they differ in frequency in different areas of the meningitis belt, and may involve any of several kinds of bacteria. One of the major causes of epidemic meningitis is Neisseria meningitidis, a meningococcus bacterium that exists in several different groups. Group A has been a common cause of epidemic meningitis in Africa, and some outbreaks were due to group C. More recently, group W135 has emerged as an epidemic strain. In addition to prompt diagnosis and treatment of individual cases, effective public health strategies for controlling meningococcal meningitis include rapid identification of outbreaks and determination of the type of bacteria involved, followed by mass vaccination of people in the surrounding area without delay. Vaccines are chosen on the basis of the responsible meningococcal serogroup: either the inexpensive bivalent vaccine A/C or the expensive, less readily available trivalent vaccine A/C/W135. Before the advent of W135 as an epidemic clone, bivalent vaccine was applied in the meningitis belt without identification of the serogroup. With the appearance of the W135 strain in 2003, however, the determination of serogroup before vaccination is important to select an effective vaccine and avoid misspending of limited funds.
Why Was This Study Done?
Because there are few laboratories in the affected countries and epidemiological surveillance systems are inadequate, it is difficult for health authorities to mount a rapid and effective vaccination campaign in response to an outbreak. In addition, because the two main bacteria (meningococcus and pneumococcus) that cause meningitis require different antibiotic treatments, it is important for doctors to find out quickly which bacteria is causing an individual case. The authors of this study wanted to develop a rapid and easy test that can tell whether meningococcus is the cause of a particular case of meningitis, and if so, which group of meningococcus is involved. As most outbreaks in the meningitis belt occur in rural areas that are distant from well-equipped medical laboratories, it was necessary to develop a test that can be carried out at the patient's bedside by nurses, does not require refrigeration or laboratory equipment, and is highly accurate in distinguishing among the different groups of meningococcus.
What Did the Researchers Do and Find?
The researchers have developed a rapid test to determine whether a patient's meningitis is caused by one of the four most common groups of meningococcus circulating in Africa. The test is done on the patient's spinal fluid, which is obtained by a lumbar puncture (spinal tap) as part of the usual evaluation of a patient thought to have meningitis. The test uses two paper strips, also called dipsticks (one for groups A and W135/Y, and the other for groups C and Y), that can be placed in two separate tubes of the patient's spinal fluid. After several minutes, the appearance of red lines on the dipsticks shows whether one of the four groups of meningococcus is present. The dipsticks can be produced in large quantities and relatively cheaply. The researchers showed that the test dipsticks are stable for weeks in hot weather, and are therefore practical for bedside use in resource-poor settings. They examined the test on stored spinal fluid from patients in Niger and found that the dipstick test was able to identify the correct group of meningococcus more than 95% of the time for the three groups represented in these specimens (the results were compared to a standard DNA test or culture that are highly accurate for identifying the type of bacteria present but much more complicated and expensive).
What Do These Findings Mean?
The new dipstick test for meningococcal meningitis represents a major advance for health-care workers in remote locations affected by meningitis epidemics. This test can be stored without refrigeration and used at bedside in the hot temperatures typical of the African savannah during the meningitis season. The dipsticks are easier to use than currently available test kits, give more rapid results, and are more accurate in telling the difference between group Y and the increasingly important group W135. Further research is needed to determine whether the test can be used with other clinical specimens (such as blood or urine), and whether the test is dependable for detecting group C meningococcus, which is common in Europe but rare in Africa. Nonetheless, the dipstick test promises to be an important tool for guiding individual treatment decisions as well as public health actions, including vaccine selection, against the perennial threat of epidemic meningitis.
Additional Information.
Please access these Web sites via the online version of this summary at
World Health Organization fact sheet on meningococcal meningitis
PATH Meningitis Vaccine Project
US Centers for Disease Control and Prevention page on meningococcal disease
PMCID: PMC1563501  PMID: 16953658
2.  Participatory Development and Analysis of a Fuzzy Cognitive Map of the Establishment of a Bio-Based Economy in the Humber Region 
PLoS ONE  2013;8(11):e78319.
Fuzzy Cognitive Mapping (FCM) is a widely used participatory modelling methodology in which stakeholders collaboratively develop a ‘cognitive map’ (a weighted, directed graph), representing the perceived causal structure of their system. This can be directly transformed by a workshop facilitator into simple mathematical models to be interrogated by participants by the end of the session. Such simple models provide thinking tools which can be used for discussion and exploration of complex issues, as well as sense checking the implications of suggested causal links. They increase stakeholder motivation and understanding of whole systems approaches, but cannot be separated from an intersubjective participatory context. Standard FCM methodologies make simplifying assumptions, which may strongly influence results, presenting particular challenges and opportunities. We report on a participatory process, involving local companies and organisations, focussing on the development of a bio-based economy in the Humber region. The initial cognitive map generated consisted of factors considered key for the development of the regional bio-based economy and their directional, weighted, causal interconnections. A verification and scenario generation procedure, to check the structure of the map and suggest modifications, was carried out with a second session. Participants agreed on updates to the original map and described two alternate potential causal structures. In a novel analysis all map structures were tested using two standard methodologies usually used independently: linear and sigmoidal FCMs, demonstrating some significantly different results alongside some broad similarities. We suggest a development of FCM methodology involving a sensitivity analysis with different mappings and discuss the use of this technique in the context of our case study. Using the results and analysis of our process, we discuss the limitations and benefits of the FCM methodology in this case and in general. We conclude by proposing an extended FCM methodology, including multiple functional mappings within one participant-constructed graph.
PMCID: PMC3820682  PMID: 24244303
3.  Fuzzy cognitive map in differential diagnosis of alterations in urinary elimination: A nursing approach 
To develop a decision support system to discriminate the diagnoses of alterations in urinary elimination, according to the nursing terminology of NANDA International (NANDA-I).
A fuzzy cognitive map (FCM) was structured considering six possible diagnoses: stress urinary incontinence, reflex urinary incontinence, urge urinary incontinence, functional urinary incontinence, total urinary incontinence and urinary retention; and 39 signals associated with them. The model was implemented in Microsoft Visual C++® Edition 2005 and applied in 195 real cases. Its performance was evaluated through the agreement test, comparing its results with the diagnoses determined by three experts (nurses). The sensitivity and specificity of the model were calculated considering the expert’s opinion as a gold standard. In order to compute the Kappa’s values we considered two situations, since more than one diagnosis was possible: the overestimation of the accordance in which the case was considered as concordant when at least one diagnoses was equal; and the underestimation of the accordance, in which the case was considered as discordant when at least one diagnosis was different.
The overestimation of the accordance showed an excellent agreement (kappa = 0.92, p < 0.0001); and the underestimation provided a moderate agreement (kappa = 0.42, p < 0.0001). In general the FCM model showed high sensitivity and specificity, of 0.95 and 0.92, respectively, but provided a low specificity value in determining the diagnosis of urge urinary incontinence (0.43) and a low sensitivity value to total urinary incontinence (0.42).
The decision support system developed presented a good performance compared to other types of expert systems for differential diagnosis of alterations in urinary elimination. Since there are few similar studies in the literature, we are convinced of the importance of investing in this kind of modeling, both from the theoretical and from the health applied points of view.
In spite of the good results, the FCM should be improved to identify the diagnoses of urge urinary incontinence and total urinary incontinence.
PMCID: PMC3768280  PMID: 22743142
Fuzzy logic; Urinary incontinence; Nursing diagnosis; Differential diagnosis
4.  Towards evidence‐based medicine for paediatricians 
To give the best care to patients and families, paediatricians need to integrate the highest‐quality scientific evidence with clinical expertise and the opinions of the family.1Archimedes seeks to assist practising clinicians by providing “evidence‐based” answers to common questions which are not at the forefront of research but are at the core of practice. In doing this, we are adapting a format that has been successfully developed by Kevin Macaway‐Jones and the group at the Emergency Medicine Journal—“BestBets”.
A word of warning. The topic summaries are not systematic reviews, although they are as exhaustive as a practising clinician can produce. They make no attempt to statistically aggregate the data, nor search the grey, unpublished literature. What Archimedes offers are practical, best evidence‐based answers to practical, clinical questions.
The format of Archimedes may be familiar. A description of the clinical setting is followed by a structured clinical question. (These aid in focusing the mind, assisting searching2 and gaining answers.3) A brief report of the search used follows—this has been carried out in a hierarchical way, to search for the best‐quality evidence to answer the question ( A table provides a summary of the evidence and key points of the critical appraisal. For further information on critical appraisal and the measures of effect (such as number needed to treat), books by Sackett et al4 and Moyer et al5 may help. To pull the information together, a commentary is provided. But to make it all much more accessible, a box provides the clinical bottom lines.
Electronic‐only topics that have been published on the BestBets site ( and may be of interest to paediatricians include:
Are meningeal irritation signs reliable in diagnosing meningitis in children?
Is immobilisation effective in Osgood‐Schlatter's disease?
Do all children presenting to the emergency department with a needlestick injury require PEP for HIV to reduce HIV transmission?
Readers wishing to submit their own questions—with best evidence answers—are encouraged to review those already proposed at If your question still has not been answered, feel free to submit your summary according to the Instructions for Authors at Three topics are covered in this issue of the journal.
Is lumbar puncture necessary for evaluation of early neonatal sepsis?
Does the use of calamine or antihistamine provide symptomatic relief from pruritus in children with varicella zoster infection?
Is supplementary iron useful when preterm infants are treated with erythropoietin?
Is more research needed?
“More research is needed” is a phrase you might have read before. But is more research really needed? Two situations are offered to us in Archimedes this month where clinical questions are, as yet, unanswered. Is iron supplementation really necessary for premature infants treated with erythropoietin, and do antihistamines and calamine lotion help in children with chicken pox? How can we decide if these questions really do “need” research? It may be worth thinking of how likely benefits and harms may be, what the importance of these outcomes are and finally, how much would you consider reasonable to pay for the answer? For example, what chance is there that antihistamines work in chickenpox? What is the chance that side effects will occur? What is the relative severity of side effects versus the delight of being itch free? If we pay for research and spend hours and hours of time pressing through the increasing regulatory frameworks for clinical trials to define the answer to this question, what will be the opportunity cost? What would we fail to do by looking at this? The same questions can be asked of iron supplementation in premature infants, the salvage treatment of relapsing systemic histocytosis or the promotion of car‐seat use in low‐income families. Such value judgements are important; they will have different answers from different perspectives; they will be subject to political influences from pressure groups; being aware of them might stop us from frequently expounding “more research is needed”.
1Moyer VA, Ellior EJ. Preface. In: Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health, Issue 1. London: BMJ Books, 2000.
2Richardson WS, Wilson MC, Nishikawa J, et al. The well‐built clinical question: a key to evidence‐based decisions. ACP J Club 1995;123:A12–13.
3Bergus GR, Randall CS, Sinift SD, et al. Does the structure of clinical questions affect the outcome of curbside consultations with specialty colleagues? Arch Fam Med 2000;9:541–7.
4Sackett DL, Starus S, Richardson WS, et al. Evidence‐based medicine. How to practice and teach EBM. San Diego: Harcourt‐Brace, 2000.
5Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health, Issue 1. London: BMJ Books, 2000.
PMCID: PMC2083019
5.  Treatment of Infections in Young Infants in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis of Frontline Health Worker Diagnosis and Antibiotic Access 
PLoS Medicine  2014;11(10):e1001741.
Anne C. C. Lee and colleagues assess the factors affecting access to treatment for neonatal and infant infections in low- and middle-income countries by conducting a systematic review and meta-analysis of frontline health worker diagnosis and access to antibiotics.
Please see later in the article for the Editors' Summary
Inadequate illness recognition and access to antibiotics contribute to high case fatality from infections in young infants (<2 months) in low- and middle-income countries (LMICs). We aimed to address three questions regarding access to treatment for young infant infections in LMICs: (1) Can frontline health workers accurately diagnose possible bacterial infection (pBI)?; (2) How available and affordable are antibiotics?; (3) How often are antibiotics procured without a prescription?
Methods and Findings
We searched PubMed, Embase, WHO/Health Action International (HAI), databases, service provision assessments (SPAs), Demographic and Health Surveys, Multiple Indicator Cluster Surveys, and grey literature with no date restriction until May 2014. Data were identified from 37 published studies, 46 HAI national surveys, and eight SPAs. For study question 1, meta-analysis showed that clinical sign-based algorithms predicted bacterial infection in young infants with high sensitivity (87%, 95% CI 82%–91%) and lower specificity (62%, 95% CI 48%–75%) (six studies, n = 14,254). Frontline health workers diagnosed pBI in young infants with an average sensitivity of 82% (95% CI 76%–88%) and specificity of 69% (95% CI 54%–83%) (eight studies, n = 11,857) compared to physicians. For question 2, first-line injectable agents (ampicillin, gentamicin, and penicillin) had low variable availability in first-level health facilities in Africa and South Asia. Oral amoxicillin and cotrimoxazole were widely available at low cost in most regions. For question 3, no studies on young infants were identified, however 25% of pediatric antibiotic purchases in LMICs were obtained without a prescription (11 studies, 95% CI 18%–34%), with lower rates among infants <1 year. Study limitations included potential selection bias and lack of neonatal-specific data.
Trained frontline health workers may screen for pBI in young infants with relatively high sensitivity and lower specificity. Availability of first-line injectable antibiotics appears low in many health facilities in Africa and Asia. Improved data and advocacy are needed to increase the availability and appropriate utilization of antibiotics for young infant infections in LMICs.
Review Registration
PROSPERO International prospective register of systematic reviews (CRD42013004586).
Please see later in the article for the Editors' Summary
Editors' Summary
Neonatal mortality—death that occurs during the first 28 days of life—accounts for nearly half of all the deaths that occur in children before they reach their fifth birthday. Worldwide, nearly 3 million neonatal deaths occur every year. Three bacterial infections—sepsis (infection of the bloodstream), pneumonia (infection of the lungs), and meningitis (infection of the brain's protective covering)—are responsible for nearly a quarter of all neonatal deaths. Babies born in low- and middle-income countries (LMICs) are at particularly high risk of developing neonatal bacterial infections because the risk factors for these infections, which include maternal infections and unhygienic delivery care, are more common in LMICs than in high-income countries. Babies born in LMICs are also at a high risk of dying from bacterial infections because access to appropriate medical care and antibiotics is often poor.
Why Was This Study Done?
To reduce neonatal deaths from bacterial infections in LMICs, health care experts need to identify the factors that limit access to medical care and antibiotics in these countries. Are babies dying because health care providers fail to diagnose neonatal bacterial infections, because antibiotics are not available in first-line health facilities, or for some other reason? In this systematic review and meta-analysis, the researchers investigate access to treatment for neonatal bacterial infections in LMICs by first asking whether frontline health workers in LMICs can accurately diagnose bacterial infections in neonates and young infants (babies less than 2 months old). Next, they ask whether antibiotics for treating neonatal infections are available and affordable in LMICs. Finally, they ask how often antibiotics are procured for young children (children up to the age of 5 years) without a prescription. A systematic review uses pre-defined criteria to identify all the research on a given topic; meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 37 published studies, 46 surveys of drug availability and affordability in LMICs (Health Access International databases), and eight surveys of the capacity of health facilities in LMICs to provide quality health care services (service provision assessments) that met their inclusion criteria. Meta-analysis of six studies indicated that a combination of simple clinical signs for the diagnosis of bacterial infection in children predicted very severe disease in young infants with a sensitivity of 87% and a specificity of 62% (“sensitivity” indicates the percentage of true positives detected by a test; “specificity” indicates the percentage of healthy people that a test correctly identifies as healthy) compared to a physician's diagnosis with laboratory testing. Meta-analysis of eight studies indicated that frontline health workers (for example, community health workers) diagnosed very severe disease (including possible bacterial infection) in young infants with a sensitivity of 82% and a specificity of 69% compared to trained physicians. The national surveys analyzed indicated that first-level (primary) health facilities in Africa and South Asia had low, variable stocks of recommended first-line injectable antibiotics and that the cost of these drugs was high. By contrast, some oral antibiotics were widely available at low cost in most regions. Finally, meta-analysis of 11 studies indicated that, in LMICs, 25% of antibiotic purchases for the treatment of young children were obtained without a prescription.
What Do These Findings Mean?
These findings suggest that trained frontline health workers should be able to identify most young infants who have possible bacterial infections in LMICs but may also diagnose bacterial infections in many young infants who are not infected. This may lead to the inappropriate use of antibiotics and facilitate the emergence of antibiotic resistance. These findings also show that the availability and affordability of first-line injectable antibiotics is low in many health facilities in Africa and Asia. The lack of neonatal-specific data on illness recognition, antibiotic formulations and availability, and other aspects of this systematic review and meta-analysis are likely to limit the accuracy of these findings. Nevertheless, the researchers suggest that, to decrease the neonatal death toll in LMICs, governments, policymakers, and the pharmaceutical industry need to work together to improve the diagnosis of neonatal bacterial infections and to increase the availability, affordability, and appropriate use of antibiotics for the treatment of these infections.
Additional Information
Please access these websites via the online version of this summary at
WHO provides information on global efforts to reduce global child mortality and on ending preventable neonatal deaths (available in several languages)
The United Nations Children's Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on global efforts to reduce child mortality , and its Childinfo website provides detailed statistics about neonatal survival and health; its “Committing to Child Survival: A Promise Renewed” webpage includes links to its 2013 progress report and to videos about ending preventable child deaths
The WHO has published a report entitled UN Commission on Life Saving Commodities for Women and Children
The Healthy Newborn Network (NHH) is an online community of more than 80 partner organizations that addresses critical knowledge gaps in newborn health; its website includes information on neonatal infections in LMICs
Kidshealth, a resource provided by the not-for-profit Nemours Foundation, has information for parents on neonatal infections (in English and Spanish)
The MedlinePlus Encyclopedia has a page on neonatal sepsis (in English and Spanish)
A personal story about fatal neonatal bacterial meningitis is available on the website of Meningitis UK, a not-for-profit organization; the site also includes a survivor story
PMCID: PMC4196753  PMID: 25314011
6.  Shifts in the Antibiotic Susceptibility, Serogroups, and Clonal Complexes of Neisseria meningitidis in Shanghai, China: A Time Trend Analysis of the Pre-Quinolone and Quinolone Eras 
PLoS Medicine  2015;12(6):e1001838.
Fluoroquinolones have been used broadly since the end of the 1980s and have been recommended for Neisseria meningitidis prophylaxis since 2005 in China. The aim of this study was to determine whether and how N. meningitidis antimicrobial susceptibility, serogroup prevalence, and clonal complex (CC) prevalence shifted in association with the introduction and expanding use of quinolones in Shanghai, a region with a traditionally high incidence of invasive disease due to N. meningitidis.
Methods and Findings
A total of 374 N. meningitidis isolates collected by the Shanghai Municipal Center for Disease Control and Prevention between 1965 and 2013 were studied. Shifts in the serogroups and CCs were observed, from predominantly serogroup A CC5 (84%) in 1965–1973 to serogroup A CC1 (58%) in 1974–1985, then to serogroup C or B CC4821 (62%) in 2005–2013. The rates of ciprofloxacin nonsusceptibility in N. meningitidis disease isolates increased from 0% in 1965–1985 to 84% (31/37) in 2005–2013 (p < 0.001). Among the ciprofloxacin-nonsusceptible isolates, 87% (27/31) were assigned to either CC4821 (n = 20) or CC5 (n = 7). The two predominant ciprofloxacin-resistant clones were designated ChinaCC4821-R1-C/B and ChinaCC5-R14-A. The ChinaCC4821-R1-C/B clone acquired ciprofloxacin resistance by a point mutation, and was present in 52% (16/31) of the ciprofloxacin-nonsusceptible disease isolates. The ChinaCC5-R14-A clone acquired ciprofloxacin resistance by horizontal gene transfer, and was found in 23% (7/31) of the ciprofloxacin-nonsusceptible disease isolates. The ciprofloxacin nonsusceptibility rate was 47% (7/15) among isolates from asymptomatic carriers, and nonsusceptibility was associated with diverse multi-locus sequence typing profiles and pulsed-field gel electrophoresis patterns. As detected after 2005, ciprofloxacin-nonsusceptible strains were shared between some of the patients and their close contacts. A limitation of this study is that isolates from 1986–2004 were not available and that only a small sample of convenience isolates from 1965–1985 were available.
The increasing prevalence of ciprofloxacin resistance since 2005 in Shanghai was associated with the spread of hypervirulent lineages CC4821 and CC5. Two resistant meningococcal clones ChinaCC4821-R1-C/B and ChinaCC5-R14-A have emerged in Shanghai during the quinolone era. Ciprofloxacin should be utilized with caution for the chemoprophylaxis of N. meningitidis in China.
Minggui Wang and colleagues assess the genetic origin and changing prevalence of N. meningitidis resistance to ciprofloxacin.
Editors' Summary
Meningitis is a viral, bacterial, or fungal infection of the meninges, the thin membrane that covers the brain and the spinal cord. Neisseria meningitidis is the most common cause of bacterial meningitis in children and is a leading cause of meningitis in adults. N. meningitidis lives harmlessly in the mucous membranes of the nose and throat of 10%–20% of human beings. These symptom-free (asymptomatic) carriers are crucial to the transmission of N. meningitidis, which spreads from person to person through droplets of respiratory or throat secretions produced by infected individuals. Although N. meningitidis usually causes no harm, it occasionally overwhelms its host’s immune system and spreads through the bloodstream and into the brain. The characteristic symptoms of meningococcal meningitis—a rash, fever, stiff neck, sensitivity to light, confusion, headaches, and vomiting—then develop rapidly. Even with early treatment with intravenous antibiotics, about 10% of the 1.2 million people affected by meningococcal meningitis every year die, usually within 24–48 hours of symptom development.
Why Was This Study Done?
Meningococcal meningitis can be prevented by vaccination against N. meningitidis. In addition, experts recommend that the family and close contacts of anyone with meningococcal meningitis be treated immediately with antibiotics to stop the disease spreading (N. meningitidis prophylaxis). The quinolone antibiotic ciprofloxacin is sometimes recommended for N. meningitidis prophylaxis, but quinolones have been used to treat many bacterial infections since the late 1980s and ciprofloxacin-resistant strains of N. meningitidis have recently emerged in some countries. Thus, policymakers in countries where ciprofloxacin may be used for meningococcal prophylaxis (for example, China, which has recommended several antibiotics, including ciprofloxacin, for meningococcal prophylaxis since 2005) need to know whether and how the susceptibility of N. meningitidis to ciprofloxacin is changing in their country. In this time trend analysis, the researchers investigate how the ciprofloxacin susceptibility, serogroup prevalence, and clonal complex prevalence of N. meningitidis have shifted in association with increasing use of quinolones in Shanghai (China), a region where many cases of meningococcal disease occur. A serogroup is a group of bacteria that carries a common antigen (a molecule recognized by the immune system); the prevalence of a serogroup is the proportion of the infected population that carries that serogroup. Only some N. meningitidis serogroups cause meningococcal disease. A clonal complex is a group of genetically related bacteria that may share genes that confer resistance to antibiotics. A strain of N. meningitidis is classified by both its serogoup and its clonal complex; the changing composition of prevalent strains can inform projections for disease spread and plans for disease management, including recommendations for prophylaxis.
What Did the Researchers Do and Find?
The researchers analyzed the characteristics of 374 N. meningitidis isolates collected in Shanghai between 1965 and 2013 from patients with meningococcal disease, their close contacts, and asymptomatic N. meningitidis carriers identified in throat swab surveys. N. meningitidis serogroups and clonal complexes (CCs) shifted from predominantly serogroup A CC5 among isolates collected in 1965–1973, to serogroup A CC1 in 1974–1985, and to serogroup C or B CC4821 in 2005–2013. Notably, the rate of nonsusceptibility to ciprofloxacin in isolates from people with meningococcal meningitis increased from 0% in 1965–1985 to 84% in 2005–2013, and 87% (27/31) of the ciprofloxacin-nonsusceptible disease isolates belonged to either CC4821 or CC5. The researchers identified the two predominant ciprofloxacin-resistant strains (designated ChinaCC4821-R1-C/B and ChinaCC5-R14-A) and showed that a different genetic alteration was responsible for the acquisition of antibiotic resistance in the two strains. Finally, the researchers report that, after 2005, the rate of ciprofloxacin nonsusceptibility among N. meningitidis isolates from asymptomatic carriers was 47%, and that some of the individuals with meningococcal meningitis shared nonsusceptible strains with their close contacts.
What Do These Findings Mean?
These findings suggest that the increased prevalence of ciprofloxacin resistance seen in Shanghai since 2005 is associated with the spread of two hypervirulent clonal complexes of N. meningitidis (CC4821 and CC5) among individuals with meningococcal disease and within the healthy population. The findings also identify two resistant meningococcal strains (ChinaCC4821-R1-C/B and ChinaCC5-R14-A) that have emerged in Shanghai since the use of quinolones to treat bacterial infections became widespread. Because this time trend analysis is based on a limited number of meningococcal isolates and because the researchers analyzed very few isolates collected between 1965 and 1985 and none collected between 1986 and 2004, this study cannot pinpoint exactly when, where, or how ciprofloxacin-resistant N. meningitidis emerged in Shanghai. Nevertheless, these findings suggest that the use of fluoroquinolones for N. meningitidis prophylaxis should be discouraged in China. Instead, the researchers suggest, physicians should turn to one of the other antibiotics recommended in China’s 2005 national scheme (for example, rifampicin) for the prevention and control of meningococcal meningitis.
Additional Information
These websites can be accessed when viewing the PDF on a device, or via the online version of this article at The US Centers for Disease Control and Prevention provide information about meningococcal diseaseThe World Health Organization has a fact sheet about meningococcal meningitisThe UK National Health Service Choices website provides information about meningitis, including some personal storiesThe non-profit Meningitis Foundation of America also provides information about meningitis and stories from survivors of meningitisMedlinePlus has links to further resources about meningitis and about meningococcal infections; the MedlinePlus Encyclopedia also provides information about meningococcal meningitis (in English and Spanish)
PMCID: PMC4461234  PMID: 26057853
7.  African meningitis belt pneumococcal disease epidemiology indicates a need for an effective serotype 1 containing vaccine, including for older children and adults 
Pneumococcal conjugate vaccine strategies in GAVI-eligible countries are focusing on infant immunization but this strategy may not be optimal in all settings. We aimed to collect all available population based data on pneumococcal meningitis throughout life in the African meningitis belt and then to model overall meningitis risk to help inform vaccine policy.
After a systematic review of literature published from 1970 through the present, we found robust population-based Streptococcus pneumoniae (Sp) meningitis data across age strata for four African meningitis belt countries that included 35 surveillance years spanning from 1970 to 2005. Using these data we modeled disease risk for a hypothetical cohort of 100,000 persons followed throughout life.
Similar to meningococcal meningitis, laboratory-confirmed pneumococcal meningitis was seasonal, occurring primarily in the dry season. The mean annual Sp meningitis incidence rates were 98, 7.8 to 14, and 5.8 to 12 per 100,000 among persons <1, 1 through 19, and 20 to 99 years of age, respectively, which (in the absence of major epidemics) were higher than meningococcal meningitis incidences for persons less than 1 and over 20 years of age. Mean Sp meningitis case fatality ratios (CFR) among hospitalized patients ranged from 36-66% depending on the age group, with CFR exceeding 60% for all age groups beyond 40 years; depending on the age group, Sp meningitis mortality incidences were 2 to 12-fold greater than those for meningococcal meningitis. The lifetime risks of pneumococcal meningitis disease and death were 0.6% (1 in 170) and 0.3% (1 in 304), respectively. The incidences of these outcomes were highest among children age <1 year. However, the cumulative risk was highest among persons age 5 to 59 years who experienced 59% of pneumococcal meningitis outcomes. After age 5 years and depending on the country, 59-79% of meningitis cases were caused by serotype 1.
In the African meningitis belt, Sp is as important a cause of meningitis as Neisseria meningitidis, particularly among older children and working age adults. The meningitis belt population needs an effective serotype 1 containing vaccine and policy discussions should consider vaccine use outside of early childhood.
PMCID: PMC2838886  PMID: 20146815
8.  Evaluation of IL-6 and High Sensitive C Reactive Protein Value in CSF and Serum Children Suspected Meningitis Referred to Pediatric Emergency Room 
Acute bacterial meningitis which is a pediatric emergency with high mortality and morbidity must be diagnosed and treat promptly. Often diagnosis of bacterial meningitis from viral meningitis is difficult after some days. Determination of some inflammatory mediators’ example IL-6 and HS-CRP were useful in differential diagnosis of bacterial and viral meningitis.
This study attempted to Determining HS-CRP and IL6 in serum and CSF in children suspected meningitis and Comparing value HS-CRP and IL6 in bacterial/viral meningitis.
Patients and Methods
Of children that hospitalized in pediatric emergency ward (Ghaem Hospital Mashhad university of medical science, in duration 01 Dec 2010-01 Dec 2011) and for they performed lumbar puncture, 1cc serum and CSF of they were taken to laboratory and have measured IL-6 with Elisa method and HS-CRP with immunoturbidometry method, patients were followed up and finally we compared levels of this two mediators.
Finally, this study performed on 81 children and infants. From 81 cases, 27 cases (33.3%) had bacterial meningitis 27 cases (33.3%) viral meningitis and 27 cases (33.3%) had normal CSF. IL-6 concentration in the CSF and serum were significantly raised in cases of bacterial meningitis (P = 0.001, P = 0.01) but HS-CRP concentration in the CSF and serum were not significantly raised in cases of bacterial meningitis (P = 0.46, P = 0.29). Mean IL-6 concentration in the CSF in bacterial meningitis was (180.74) and in viral meningitis was (39.08) .Mean HS-CRP in CSF in bacterial meningitis was (2.22) and viral meningitis was (1.29). Mean HS-CRP in serum in bacterial meningitis was (8.23) and viral meningitis was (6.36).
The measurement of IL-6 in the CSF and serum in potentially a very useful diagnostic tool for differential diagnosis of bacterial and viral meningitis.
PMCID: PMC3587874  PMID: 23483792
Interleukin-6; Meningitis; Child
9.  Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites 
PLoS Medicine  2014;11(7):e1001685.
Mary Hamel and colleagues in the RTS,S Clinical Trials Partnership report updated safety and efficacy results from an ongoing Phase 3 trial, including calculations of vaccine impact (malaria cases prevented).
Please see later in the article for the Editors' Summary
A malaria vaccine could be an important addition to current control strategies. We report the safety and vaccine efficacy (VE) of the RTS,S/AS01 vaccine during 18 mo following vaccination at 11 African sites with varying malaria transmission.
Methods and Findings
6,537 infants aged 6–12 wk and 8,923 children aged 5–17 mo were randomized to receive three doses of RTS,S/AS01 or comparator vaccine.
VE against clinical malaria in children during the 18 mo after vaccine dose 3 (per protocol) was 46% (95% CI 42% to 50%) (range 40% to 77%; VE, p<0.01 across all sites). VE during the 20 mo after vaccine dose 1 (intention to treat [ITT]) was 45% (95% CI 41% to 49%). VE against severe malaria, malaria hospitalization, and all-cause hospitalization was 34% (95% CI 15% to 48%), 41% (95% CI 30% to 50%), and 19% (95% CI 11% to 27%), respectively (ITT).
VE against clinical malaria in infants was 27% (95% CI 20% to 32%, per protocol; 27% [95% CI 21% to 33%], ITT), with no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization.
Post-vaccination anti-circumsporozoite antibody geometric mean titer varied from 348 to 787 EU/ml across sites in children and from 117 to 335 EU/ml in infants (per protocol).
VE waned over time in both age categories (Schoenfeld residuals p<0.001). The number of clinical and severe malaria cases averted per 1,000 children vaccinated ranged across sites from 37 to 2,365 and from −1 to 49, respectively; corresponding ranges among infants were −10 to 1,402 and −13 to 37, respectively (ITT). Meningitis was reported as a serious adverse event in 16/5,949 and 1/2,974 children and in 9/4,358 and 3/2,179 infants in the RTS,S/AS01 and control groups, respectively.
RTS,S/AS01 prevented many cases of clinical and severe malaria over the 18 mo after vaccine dose 3, with the highest impact in areas with the greatest malaria incidence. VE was higher in children than in infants, but even at modest levels of VE, the number of malaria cases averted was substantial. RTS,S/AS01 could be an important addition to current malaria control in Africa.
Trial registration NCT00866619
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, more than 200 million cases of malaria occur worldwide, and more than 600,000 people, mainly children living in sub-Saharan Africa, die from this parasitic disease. Malaria parasites are transmitted to people through the bites of infected night-flying mosquitoes and cause fever that needs to be treated promptly with anti-malarial drugs to prevent anemia (a reduction in red blood cell numbers) and life-threatening organ damage. Malaria transmission can be prevented by using long-lasting insecticides sprayed on the indoor walls of homes to kill the mosquitoes that spread the malaria parasite or by sleeping under insecticide-treated nets to avoid mosquito bites and further reduce mosquito numbers. Widespread use of these preventative measures, together with the introduction of artemisinin combination therapy (an effective anti-malarial treatment), has reduced the global burden of malaria by 45% in all age groups, and by 51% among young children, since 2000.
Why Was This Study Done?
Unfortunately, the emergence of insecticide and drug resistance is threatening this advance in malaria control. Moreover, additional interventions—specifically, effective malaria vaccines—will be needed to eliminate malaria in the large areas of Africa where malaria transmission remains high. Currently, there is no licensed malaria vaccine, but RTS,S/AS01, the most advanced malaria vaccine candidate, is undergoing phase 3 clinical trials (the last stage of testing before licensing) in infants and children in seven African countries. The RTS,S Clinical Trials Partnership reported encouraging results on the efficacy and safety of RTS,S/AS01 during 12 months of follow-up in 2011 and 2012. Here, researchers report on the 18-month efficacy and safety of RTS,S/AS01. Vaccine efficacy (VE) is the reduction in the incidence of a disease (the number of new cases that occur in a population in a given period) among trial participants who receive the vaccine compared to the incidence among participants who do not receive the vaccine.
What Did the Researchers Do and Find?
The researchers randomly assigned 6,537 infants aged 6–12 weeks and 8,923 children aged 5–17 months to receive three doses of RTS,S/AS01 or a control vaccine. During 18 months of follow-up, there were 0.69 episodes of clinical malaria (a high temperature and parasites in the blood) per person-year among the children who received all the planned doses of RTS,S/AS01 (the “per protocol” population) and 1.17 episodes per person-year among the control children—a VE against clinical malaria in the per-protocol population of 46%. A similar VE was seen in an intention-to-treat analysis that included all the enrolled children, regardless of whether they received all of the planned vaccine doses; intention-to-treat analyses reflect the real-life situation—in which children sometimes miss vaccine doses—better than per-protocol analyses. In intention-to-treat analyses, the VE among children against severe malaria (fever, parasites in the blood, and symptoms such as anemia) and hospitalization for malaria was 34% and 41%, respectively. Among infants, the VE against clinical malaria was 27% in both per-protocol and intention-to-treat analyses; the vaccine showed no protection against severe malaria or hospitalization. In both infants and children, VE waned with time since vaccination. Across all the study sites, RTS,S/AS01 averted an average of 829 and 449 cases of clinical malaria per 1,000 children and infants vaccinated, respectively. Finally, the serious adverse event meningitis (inflammation of the tissues lining the brain and spinal cord) occurred more frequently in trial participants given RTS,S/AS01 than in those given the control vaccine, but the incidence of other serious adverse events was similar in both groups of participants.
What Do These Findings Mean?
These and other findings show that, during 18 months of follow-up, vaccination of children and young infants with RTS,S/AS01 prevented many cases of clinical and severe malaria and that the impact of vaccination was highest in regions with the highest incidence of malaria. They indicate, as in the earlier analysis, that the VE against clinical and severe malaria is higher in children than in young infants and suggest that protection wanes over time. Whether or not the vaccine played a causal role in the observed cases of meningitis cannot be determined from these results, and the occurrence of meningitis will be followed closely during the remainder of the trial. Other study limitations (for example, variations in the clinical characteristics of participants from one center to another) may also affect the accuracy of these findings and their interpretation. However, by showing that even a modest VE can avert a substantial number of malaria cases, these findings suggest that vaccination with RTS,S/AS01 could have a major public health impact in sub-Saharan Africa.
Additional Information
Please access these websites via the online version of this summary at
Information is available from the World Health Organization on all aspects of malaria (in several languages), including malaria immunization; the World Malaria Report 2013 provides details of the current global malaria situation; the World Health Organization also provides information on its Global Immunization Vision and Strategy (in English and French)
The US Centers for Disease Control and Prevention provides information on malaria, including a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria and on the Global Malaria Action Plan (in English and French); its website includes a fact sheet about malaria in Africa
The latest results from the phase 3 trial of RTS,S are available on the website of the PATH Malaria Vaccine Initiative, a global program of the international nonprofit organization PATH that aims to accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world
MedlinePlus provides links to additional information on malaria and on immunization (in English and Spanish)
PMCID: PMC4114488  PMID: 25072396
10.  Defining Childhood Severe Falciparum Malaria for Intervention Studies 
PLoS Medicine  2007;4(8):e251.
Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials. Although there is no “gold standard” individual test for severe malaria, malaria-attributable fractions (MAFs) can be estimated among groups of children using a logistic model, which we use to test the suitability of various case definitions as trial endpoints.
Methods and Findings
A total of 4,583 blood samples were taken from well children in cross-sectional surveys and from 1,361 children admitted to a Kenyan District hospital with severe disease. Among children under 2 y old with severe disease and over 2,500 parasites per microliter of blood, the MAFs were above 85% in moderate- and low-transmission areas, but only 61% in a high-transmission area. HIV and malnutrition were not associated with reduced MAFs, but gastroenteritis with severe dehydration (defined by reduced skin turgor), lower respiratory tract infection (clinician's final diagnosis), meningitis (on cerebrospinal fluid [CSF] examination), and bacteraemia were associated with reduced MAFs. The overall MAF was 85% (95% confidence interval [CI] 83.8%–86.1%) without excluding these conditions, 89% (95% CI 88.4%–90.2%) after exclusions, and 95% (95% CI 94.0%–95.5%) when a threshold of 2,500 parasites/μl was also applied. Applying a threshold and exclusion criteria reduced sensitivity to 80% (95% CI 77%–83%).
The specificity of a case definition for severe malaria is improved by applying a parasite density threshold and by excluding children with meningitis, lower respiratory tract infection (clinician's diagnosis), bacteraemia, and gastroenteritis with severe dehydration, but not by excluding children with HIV or malnutrition.
The accepted definition of severe malaria is appropriate for clinical purposes, but Philip Bejon and colleagues show its specificity in clinical trials may be improved by a parasite density threshold and by excluding children with certain conditions.
Editors' Summary
Malaria is responsible for over a million deaths every year, and most of those who die are children in Africa. Until a few years ago, not enough research was being done on malaria, but now many researchers are active in this field. Doctors describe some cases of malaria as being “severe.” Severe malaria in children is very hard to diagnose precisely. Current protocols for diagnosing severe malaria are very sensitive: that is, virtually all children who do have severe malaria will be correctly diagnosed as such. However, the protocols are not very specific: many children who do not have severe malaria, but whose symptoms are instead caused by other diseases, will be defined as suffering from severe malaria. This definition is acceptable for the clinical care of sick children, because it ensures that antimalarial drugs are given to all who might benefit from them, plus some additional children for whom those drugs are not required. However, this definition is not particularly useful for research purposes. When conducting a clinical trial aimed at preventing cases of malaria, it is important to evaluate whether the intervention being tested actually works. Therefore, a more specific method of calculating the number of malaria cases within a population is needed for this type of research.
Why Was This Study Done?
The current definition for diagnosing severe malaria includes a set of signs and symptoms that may be observed at the bedside or as a result of laboratory investigation, along with the detection of malaria parasites in the patient's blood. However, in many malarious areas, a large proportion of the population carries malaria parasites without signs of disease; at the same time, the signs and symptoms of malaria are shared with other diseases. The investigators here wanted to find out whether they could develop an accurate “case definition” of severe malaria that can be used in research.
What Did the Researchers Do and Find?
In this study, two groups of children were studied: first, 1,422 children admitted to the children's wards of the Kilifi District Hospital in Kenya, and second, 4,583 children from the surrounding community. Blood samples were taken in order to find out how common malaria parasites were in the children's blood, and standard clinical and laboratory data were also collected from the children admitted to the hospital. The researchers then compared these data using a computer and tried to find out whether, by excluding certain children who had particular signs, symptoms, or observations, from the diagnosis of severe malaria, they were able to improve the accuracy of their definition. Essentially, for each patient group, the authors calculated “malaria-attributable fractions,” i.e., the proportion of individuals studied whose disease was likely caused by malaria.
The researchers found that in areas with low and moderate transmission of malaria, the proportion of individuals whose disease could be attributed to malaria was high—nearly 85%. In areas with a high transmission rate of malaria, this fraction was much lower, but could be improved by including only children with a high proportion of parasites in their blood. Importantly, the researchers were also able to increase the recognition of children with disease likely caused by malaria by excluding individuals who had also been diagnosed with gastroenteritis, lower respiratory tract infections, meningitis, and bacterial infection in the blood. If all of these individuals were excluded—so only individuals with more than 2,500 parasites per microliter in their blood were regarded as having severe malaria—the “malaria-attributable fraction” rose to 95%.
What Do These Findings Mean?
These findings should not be directly used to change the clinical care of children with the signs and symptoms of severe malaria, but rather can be used within a clinical trial to create a “case definition” of malaria particular to that trial. This ability will help researchers more accurately find out whether the intervention being tested in their trial really does help to prevent cases of malaria or not.
Additional Information.
Please access these Web sites via the online version of this summary at
The World Health Organization Global Malaria Programme details the organization's activities in fighting malaria, and provides a number of helpful resources; a factsheet on children and malaria is also available
The US Centers for Disease Control and Prevention provides many malaria resources
General information about malaria, including illustrations, is available from the“Medline Plus” encyclopedia
PMCID: PMC1949845  PMID: 17713980
11.  Testing for Meningitis in Children with Bronchiolitis 
The Permanente Journal  2014;18(4):16-19.
The authors present a retrospective, case-control study of hospitalized infants younger than age one year diagnosed with viral bronchiolitis who underwent lumbar puncture as part of an evaluation for meningitis. The presence of apnea, cyanosis, meningeal signs, positive urine culture results, and young age were factors found to be preliminarily associated with the performance of a lumbar puncture in the setting of bronchiolitis. Young age was the only significant clinical factor found after multivariable regression; no other demographic, clinical, laboratory, or radiologic variables were found to be significant.
Viral bronchiolitis accounts for almost 20% of all-cause hospitalizations of infants (ie, children younger than age 1 year). The annual incidence of fever in viral bronchiolitis has been documented at 23% to 31%. However the incidence of concurrent serious bacterial infections is low (1%–7%), with meningitis occurring in less than 1% to 2% of cases, but lumbar puncture is performed in up to 9% of viral bronchiolitis cases. To our knowledge, no study has examined clinical factors that influence a physician’s decision to perform a lumbar puncture in the setting of viral bronchiolitis.
We present a retrospective, case-control study of hospitalized infants younger than one year diagnosed with viral bronchiolitis who underwent lumbar puncture as part of an evaluation for meningitis. The objective of the study was to determine clinical factors that influence a physician’s decision to perform a lumbar puncture in the setting of viral bronchiolitis. Although the presence of apnea, cyanosis, meningeal signs, positive urine culture results, and young age were factors found to be preliminarily associated with the performance of a lumbar puncture in the setting of bronchiolitis, young age was the only significant clinical factor found after multivariable regression; no other demographic, clinical, laboratory, or radiologic variables were found to be significant.
PMCID: PMC4206166  PMID: 25662522
12.  Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis 
PLoS Medicine  2012;9(9):e1001316.
David Boulware and colleagues assess the cost effectiveness of different treatment strategies in low- and middle-income countries for cryptococcal meningitis, one of the most common opportunistic infections of people with HIV.
Cryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations.
Methods and Findings:
We conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800–1,200 mg/d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resource-limited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to $467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to $44 per QALY. Overall, amphotericin-based regimens had higher costs but better survival. Short-course amphotericin (1 mg/kg/d for 7 d) with fluconazole (1,200 mg/d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24/QALY, with an ICER of $15.11 per additional QALY over fluconazole monotherapy. The main limitation of this study is the pooled nature of a systematic review, with a paucity of outcome data with direct comparisons between regimens.
Short-course (7-d) amphotericin induction therapy coupled with high-dose (1,200 mg/d) fluconazole is “very cost effective” per World Health Organization criteria and may be a worthy investment for policy-makers seeking cost-effective clinical outcomes. More head-to-head clinical trials are needed on treatments for this neglected tropical disease.
Please see later in the article for the Editors' Summary.
Editors' Summary
Cryptococcal meningitis, a fungal infection of the membranes around the brain and spinal cord, affects about a million people every year (most of them living in sub-Saharan Africa and Southeast Asia) and kills about 640,000 people annually. People become infected with Cryptococcus neoformans, the fungus that causes cryptococcal meningitis and which is found in soil and dirt, by breathing it in. In healthy individuals, infection rarely causes disease. But in people living with AIDS, whose immune system has been damaged by HIV infection, and in people whose immune system is compromised for other reasons, the fungus can invade and damage many organs, including the brain. Cryptococcal meningitis, the symptoms of which include fever, stiff neck, headache, and vomiting, is diagnosed by looking for the fungus in fluid taken from the spinal cord in a procedure called a lumbar puncture. Cryptococcal meningitis is treated with antifungal drugs such as amphotericin, fluconazole, and flucytosine (induction therapy); recurrence of the infection is prevented by taking fluconazole daily for life or until the immune system recovers.
Why Was This Study Done?
The World Health Organization (WHO) recommends a 14-day regimen of intravenous (injected) amphotericin and oral flucytosine or fluconazole for induction therapy of cryptococcal meningitis. Unfortunately, this regimen is impractical in many resource-limited settings because of the cost of the drugs and hospital care and the need for intensive monitoring—amphotericin is extremely toxic. Consequently, high-dose fluconazole monotherapy is the usual treatment for cryptococcal meningitis in resource-limited countries, although this regimen is much less effective. Another regimen that has improved survival in trials is flucytosine with fluconazole for two weeks. However, flucytosine is very expensive and is not licensed in most sub-Saharan African countries. Stakeholders in developing countries badly need guidance, therefore, on which induction treatment for cryptococcal meningitis they should recommend to optimize outcomes in their particular countries. In this cost-effectiveness analysis (a study that compares the costs and health effects of different interventions), the researchers use costs in Uganda to estimate the survival, cost, and cost per benefit associated with various induction treatments for cryptococcal meningitis in HIV-infected patients.
What Did the Researchers Do and Find?
The researchers calculated the overall cost of six induction treatments using 2012 healthcare costs in Uganda for medications, supplies, and hospital care, and average laboratory costs for monitoring treatment from three African countries. They used data from published trials of cryptococcal meningitis treatment in resource-limited areas to estimate ten-week and one-year survival, life expectancy, and quality-adjusted life years (QALYs, the number of years of life added by an intervention, adjusted for the quality of life) for each intervention. Finally, they calculated the cost-effectiveness ratio (cost per QALY gained) and the incremental cost effectiveness ratio (ICER, the additional cost of a treatment strategy compared to fluconazole monotherapy divided by the incremental improvement in QALYs) for each intervention. The estimated costs per person for each induction treatment strategy ranged from US$154 for 14 days of fluconazole monotherapy to US$467 for 14 days of amphotericin plus flucytosine. Estimated average one-year survival was lowest for fluconazole (40%) and highest for short-course (seven days) amphotericin plus 14 days of fluconazole (66%), similar to other amphotericin-based treatments. Cost-effectiveness ratios ranged from US$20 per QALY for short-course amphotericin plus fluconazole to US$44 per QALY for 14 days of amphotericin plus flucytosine. Short-course amphotericin plus fluconazole had the lowest ICER (US$15.11 per additional QALY over fluconazole monotherapy).
What Do These Findings Mean?
These findings suggest that, among the treatments investigated, a seven-day course of amphotericin with high-dose fluconazole for at least two weeks is the most cost-effective induction treatment for cryptococcal meningitis in Uganda. Although this result should be generalizable to other African countries, it needs to be treated with caution because very few trials have actually looked at the clinical effectiveness of this particular regimen. While short short-course amphotericin appears to be substantially more effective than fluconazole monotherapy, large-scale trials comparing short-course amphotericin regimens with more traditional 14-day regimens in resource-limited countries must be undertaken before short-course amphotericin-based treatments are adopted. Notably, however, if these trials confirm that survival with short-course amphotericin with fluconazole is about 30% better than with fluconazole alone, the researchers calculate that moving to short-course amphotericin could save about 150,000 lives every year in sub-Saharan Africa at a cost of US$220 per life saved.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Andrew Farlow provides a clearinghouse for updated guidelines for cryptococcal diagnosis and treatment.
The US Centers for Disease Control and Prevention provides information on Cryptococcus neoformans and a training manual called the Cryptococcal Screening Program Training Manual for Healthcare Providers
NAM/aidsmap provides information about all aspects of infection with Cryptococcus neoformans, including a personal story about cryptococcal meningitis
AIDS InfoNet has a fact sheet on cryptococcal meningitis (in several languages)
The not-for-profit organization Project Inform, which provides information, inspiration, and advocacy for people with HIV/AIDS and hepatitis C (in English and Spanish), has a fact sheet on cryptococcal meningitis
The MedlinePlus encyclopedia has a page on cryptococcal meningitis (in English and Spanish)
PMCID: PMC3463510  PMID: 23055838
13.  Diagnostic Accuracy of Quantitative PCR (Xpert MTB/RIF) for Tuberculous Meningitis in a High Burden Setting: A Prospective Study 
PLoS Medicine  2013;10(10):e1001536.
Vinod Patel and colleagues evaluate the sensitivity and specificity of quantitative PCR using Xpert MTB/RIF for diagnosis of TB meningitis in the high-burden setting of South Africa.
Please see later in the article for the Editors' Summary
Tuberculous meningitis (TBM) is difficult to diagnose promptly. The utility of the Xpert MTB/RIF test for the diagnosis of TBM remains unclear, and the effect of host- and sample-related factors on test performance is unknown. This study sought to evaluate the sensitivity and specificity of Xpert MTB/RIF for the diagnosis of TBM.
Methods and Findings
235 South-African patients with a meningeal-like illness were categorised as having definite (culture or Amplicor PCR positive), probable (anti-TBM treatment initiated but microbiological confirmation lacking), or non-TBM. Xpert MTB/RIF accuracy was evaluated using 1 ml of uncentrifuged and, when available, 3 ml of centrifuged cerebrospinal fluid (CSF). To evaluate the incremental value of MTB/RIF over a clinically based diagnosis, test accuracy was compared to a clinical score (CS) derived using basic clinical and laboratory information.
Of 204 evaluable patients (of whom 87% were HIV-infected), 59 had definite TBM, 64 probable TBM, and 81 non-TBM. Overall sensitivity and specificity (95% CI) were 62% (48%–75%) and 95% (87%–99%), respectively. The sensitivity of Xpert MTB/RIF was significantly better than that of smear microscopy (62% versus 12%; p = 0.001) and significantly better than that of the CS (62% versus 30%; p = 0.001; C statistic 85% [79%–92%]). Xpert MTB/RIF sensitivity was higher when centrifuged versus uncentrifuged samples were used (82% [62%–94%] versus 47% [31%–61%]; p = 0.004). The combination of CS and Xpert MTB/RIF (Xpert MTB/RIF performed if CS<8) performed as well as Xpert MTB/RIF alone but with a ∼10% reduction in test usage. This overall pattern of results remained unchanged when the definite and probable TBM groups were combined. Xpert MTB/RIF was not useful in identifying TBM among HIV-uninfected individuals, although the sample was small. There was no evidence of PCR inhibition, and the limit of detection was ∼80 colony forming units per millilitre. Study limitations included a predominantly HIV-infected cohort and the limited number of culture-positive CSF samples.
Xpert MTB/RIF may be a good rule-in test for the diagnosis of TBM in HIV-infected individuals from a tuberculosis-endemic setting, particularly when a centrifuged CSF pellet is used. Further studies are required to confirm these findings in different settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Worldwide, tuberculosis (TB) is the leading cause of death among people living with HIV. The risk of developing TB is estimated to be 12–20 times greater in people with HIV than in people without HIV. The World Health Organization reported that, in 2011, there were 8.7 million new cases of TB, of which 1.1 million were among people living with HIV. TB infection in people living with HIV is a major problem in sub-Saharan Africa, where up to 80% of individuals infected with TB are also infected with HIV.
TB is caused by a bacterial infection spread through the air from one person to another when the infected person coughs or sneezes, for example. It usually affects the lungs, but it can also affect other parts of the body including the brain, where it leads to meningitis. People with meningitis caused by TB are often seriously ill. Many may develop brain damage, and 30% will die, particularly if they aren't diagnosed quickly and treatment is delayed. TB meningitis is therefore a serious health concern in countries with high rates of HIV and TB co-infection.
Why Was This Study Done?
There is currently no simple test to diagnose TB meningitis. The tests that are available detect only about 50% of cases. They are expensive and practical to use only in a high-tech environment, and are therefore unsuitable for low-income countries.
Recently, a new test has become available to detect TB, known as Xpert MTB/RIF. The test is used to detect the DNA (the molecular biological instructions for each organism) of the bacteria that causes TB. It is accurate at detecting TB lung infection, requires minimal training to operate, and is relatively inexpensive. It is now being used to diagnose TB in countries with high rates of the disease, including South Africa. However, thus far its use has been limited to detecting the TB bacterium in sputum samples (a mixture of saliva and phlegm) from people with a lung infection. The few studies that have assessed whether the test can be used to detect TB meningitis have been small and inconclusive.
This study was carried out to determine whether Xpert MTB/RIF could be used to detect TB bacteria in the cerebrospinal fluid (the fluid that surrounds the brain and spinal cord) in people with TB meningitis. The researchers wanted to find out whether the test would be sensitive (correctly identifying patients with TB meningitis) and specific (correctly identifying patients without TB meningitis). They also wanted to address more practical questions such as how much cerebrospinal fluid needs to be collected and how the sample needs to be processed to ensure accurate results.
What Did the Researchers Do and Find?
The researchers used the Xpert MTB/RIF test to analyze cerebrospinal fluid samples from 204 patients with suspected TB meningitis. These patients were recruited from hospitals in South Africa between January 2008 and December 2011.
Standard diagnostic tests were used to categorize these patients as either definitely having TB meningitis, possibly having TB meningitis, or not having TB meningitis. Among patients infected with HIV, the Xpert MTB/RIF correctly identified 62% of those with TB meningitis and 95% of those without TB meningitis.
The researchers also assessed whether it would be more cost-effective to use the test only for cases where the standard diagnostic procedure was uncertain, i.e., to avoid testing in cases where TB meningitis was very likely following the normal clinical assessment. Based on the researchers' theoretical analysis, this would reduce test use by only about 10%.
What Do These Findings Mean?
This study suggests that Xpert MTB/RIF is a useful diagnostic test for TB meningitis in patients infected with HIV living in areas where there are high levels of TB infection. It is not known how well the test would perform in places where TB levels are low, and the test did not perform well in individuals without HIV, although there were very few of these patients. The Xpert MTB/RIF test correctly identified more positive cases than the other tests used to diagnose TB meningitis, within 24 hours of first seeing a patient. However, the test accuracy was best when the cerebrospinal fluid sample was centrifuged (spinning the sample very fast to concentrate the test material) to achieve the best results. This means additional apparatus would be required, resulting in higher cost and requiring more training. The researchers conclude that this test could still be useful in settings where resources are limited.
There are also important questions that remain unanswered. This study shows only that the Xpert MTB/RIF test is useful in determining that a patient has TB meningitis. It is not useful in determining that a patient does not have TB meningitis. Further research is needed to determine whether the test will be effective in areas with lower rates of TB, as well as whether its use will improve clinical practice and ultimately lead to better outcomes for patients. The hope is that the test will result in more rapid diagnosis and faster treatment, reducing the number of avoidable deaths from TB meningitis.
Additional Information
Please access these websites via the online version of this summary at
• This study is further discussed in a PLOS Medicine Perspective by David Boulware
• The US National Institutes of Health provides information on TB meningitis
• The World Health Organization provides information on tuberculosis and HIV
• The US Centers for Disease Control and Prevention has a factsheet on HIV and TB
• also provides information about HIV and TB
PMCID: PMC3805498  PMID: 24167451
14.  Frequency of Meningitis in Children Presenting with Febrile Seizures at Ali-Asghar Children’s Hospital 
Febrile seizures (FS) are the most common type of childhood seizures, affecting 2–5% of children. As the seizure may be the sole presentation of bacterial meningitis in febrile infants, it is mandatory to exclude underlying meningitis in children presenting with fever and seizure. To determine the frequency of meningitis in children with FS and related risk factors, the present study was conducted at Ali-Asghar Children’s Hospital.
Materials & Methods
The records of children aged from 1-month–6 years of age with fever and seizure admitted to the hospital from October 2000–2010 were studied. The charts of patients who had undergone a lumbar puncture were studied and cases of meningitis were selected. The related data was collected and analyzed with SPSS version 16.
A total of 681 patients with FS were known from which 422 (62%) lumbar punctures (LP) were done. Meningitis (bacterial or aseptic) was identified in 19 cases (4.5%, 95% CI 2.9–6.9 by Wilson- Score internal) and bacterial meningitis in 7 (1.65%, 95% CI 0.8–3.3). None of the patients with bacterial meningitis had meningeal irritation signs. Complex FS, first attack of FS, and impaired consciousness were more common in patients with meningitis when compared to non- meningitis patients.
Meningitis is more common in patients less than 18 months presenting with FS; however, complex features of seizures, first attack of FS, or impaired consciousness seem significant risk factors for meningitis in these children and an LP should be considered in this situation.
PMCID: PMC4308616  PMID: 25663842
Bacterial meningitis; Febrile seizure; Meningitis
15.  Analyzing the impact of social factors on homelessness: a Fuzzy Cognitive Map approach 
The forces which affect homelessness are complex and often interactive in nature. Social forces such as addictions, family breakdown, and mental illness are compounded by structural forces such as lack of available low-cost housing, poor economic conditions, and insufficient mental health services. Together these factors impact levels of homelessness through their dynamic relations. Historic models, which are static in nature, have only been marginally successful in capturing these relationships.
Fuzzy Logic (FL) and fuzzy cognitive maps (FCMs) are particularly suited to the modeling of complex social problems, such as homelessness, due to their inherent ability to model intricate, interactive systems often described in vague conceptual terms and then organize them into a specific, concrete form (i.e., the FCM) which can be readily understood by social scientists and others. Using FL we converted information, taken from recently published, peer reviewed articles, for a select group of factors related to homelessness and then calculated the strength of influence (weights) for pairs of factors. We then used these weighted relationships in a FCM to test the effects of increasing or decreasing individual or groups of factors. Results of these trials were explainable according to current empirical knowledge related to homelessness.
Prior graphic maps of homelessness have been of limited use due to the dynamic nature of the concepts related to homelessness. The FCM technique captures greater degrees of dynamism and complexity than static models, allowing relevant concepts to be manipulated and interacted. This, in turn, allows for a much more realistic picture of homelessness. Through network analysis of the FCM we determined that Education exerts the greatest force in the model and hence impacts the dynamism and complexity of a social problem such as homelessness.
The FCM built to model the complex social system of homelessness reasonably represented reality for the sample scenarios created. This confirmed that the model worked and that a search of peer reviewed, academic literature is a reasonable foundation upon which to build the model. Further, it was determined that the direction and strengths of relationships between concepts included in this map are a reasonable approximation of their action in reality. However, dynamic models are not without their limitations and must be acknowledged as inherently exploratory.
PMCID: PMC3766254  PMID: 23971944
Homelessness; Complex social system; Fuzzy logic; Fuzzy Cognitive Map; Network analysis
16.  Evaluation of a Rapid and Completely Automated Real-Time Reverse Transcriptase PCR Assay for Diagnosis of Enteroviral Meningitis▿ 
Journal of Clinical Microbiology  2011;49(2):528-533.
Nucleic acid amplification tests (NAATs) for enterovirus RNA in cerebrospinal fluid (CSF) have emerged as the new gold standard for diagnosis of enteroviral meningitis, and their use can improve the management and decrease the costs for caring for children with enteroviral meningitis. The Xpert EV assay (Cepheid, Sunnyvale, CA) is a rapid, fully automated real-time PCR test for the detection of enterovirus RNA that was approved by the U.S. Food and Drug Administration for in vitro diagnostic use in March 2007. In this multicenter trial we established the clinical performance characteristics of the Xpert EV assay in patients presenting with meningitis symptoms relative to clinical truth. Clinical truth for enteroviral meningitis was defined as clinical evidence of meningitis, the absence of another detectable pathogen in CSF, and detection of enterovirus in CSF either by two reference NAATs or by viral culture. A total of 199 prospectively and 235 retrospectively collected specimens were eligible for inclusion in this study. The overall prevalence of enteroviral meningitis was 26.04%. The Xpert EV assay had a sensitivity of 94.69% (90% confidence interval [CI] = 89.79 to 97.66%), specificity of 100% (90% CI = 99.07 to 100%), positive predictive value of 100%, negative predictive value of 98.17, and an accuracy of 98.62% relative to clinical truth. The Xpert EV assay demonstrated a high degree of accuracy for diagnosis of enteroviral meningitis. The simplicity and on-demand capability of the Xpert EV assay should prove to be a valuable adjunct to the evaluation of suspected meningitis cases.
PMCID: PMC3043510  PMID: 21159942
17.  Paediatric palliative home care in areas of Germany with low population density and long distances: a questionnaire survey with general paediatricians 
BMC Research Notes  2012;5:498.
In 2007, the patient’s right to specialised palliative home care became law in Germany. However, childhood palliative care in territorial states with low patient numbers and long distances requires adapted models to ensure an area-wide maintenance. Actually, general paediatricians are the basic care providers for children and adolescents. They also provide home care. The aim of this study was to improve the knowledge about general paediatrician’s involvement in and contribution to palliative care in children.
To evaluate the current status of palliative home care provided by general paediatricians and their cooperation with other paediatric palliative care providers, a questionnaire survey was disseminated to general paediatricians in Lower Saxony, a German federal state with nearly eight million inhabitants and a predominantly rural infrastructure. Data analysis was descriptive.
One hundred forty one of 157 included general paediatricians completed the questionnaire (response rate: 89.8%). A total of 792 children and adolescents suffering from life-limiting conditions were cared for by these general paediatricians in 2008. Severe cerebral palsy was the most prevalent diagnosis. Eighty-nine per cent of the general paediatricians stated that they had professional experience with paediatric palliative care.
Collaboration of general paediatricians and other palliative care providers was stated as not well developed. The support by a specialised team including 24-hour on-call duty and the intensification of educational programs were emphasised.
The current regional infrastructure of palliative home care in Lower Saxony can benefit from the establishment of a coordinated network of palliative home care providers.
PMCID: PMC3532334  PMID: 22967691
Children; Palliative care; Paediatrician’s survey; Home care; Network; Prevalence
18.  Linking Surveillance to Action: Incorporation of Real-time Regional Data into a Medical Decision Rule 
Broadly, to create a bidirectional communication link between public health surveillance and clinical practice. Specifically, to measure the impact of integrating public health surveillance data into an existing clinical prediction rule. We incorporate data about recent local trends in meningitis epidemiology into a prediction model differentiating aseptic from bacterial meningitis.
Design and Measurements
Retrospective analysis of a cohort of all 696 children with meningitis admitted to a large urban pediatric hospital from 1992 to 2000. We modified a published bacterial meningitis score by adding a new epidemiological context adjustor variable. We examined 540 possible rules for this adjustor, varying both the number of aseptic meningitis cases that needed to be seen, and the recent time window in which they were seen. We performed sensitivity analyses with each of 540 possibilities in order to identify the optimal rule—namely, the one that included the most cases of aseptic meningitis without missing additional cases of bacterial meningitis, as compared with the published prediction model. We used bootstrap methods to validate this new score.
The optimal rule was found to be: “at least four cases of aseptic meningitis in the previous 10 days.” The epidemiological context adjustor based on surveillance of recent cases of meningitis allowed the correct identification of an additional 47 cases (7%) of aseptic meningitis without missing any additional cases of bacterial meningitis. The epidemiological context adjustor was validated, showing significance in 84% of 1,000 bootstrap samples.
Epidemiological contextual information can improve the performance of a clinical prediction rule. We provide a methodological framework for leveraging regional surveillance data to improve medical decision-making.
PMCID: PMC2213475  PMID: 17213492
19.  Sequelae due to bacterial meningitis among African children: a systematic literature review 
BMC Medicine  2009;7:47.
African children have some of the highest rates of bacterial meningitis in the world. Bacterial meningitis in Africa is associated with high case fatality and frequent neuropsychological sequelae. The objective of this study is to present a comprehensive review of data on bacterial meningitis sequelae in children from the African continent.
We conducted a systematic literature search to identify studies from Africa focusing on children aged between 1 month to 15 years with laboratory-confirmed bacterial meningitis. We extracted data on neuropsychological sequelae (hearing loss, vision loss, cognitive delay, speech/language disorder, behavioural problems, motor delay/impairment, and seizures) and mortality, by pathogen.
A total of 37 articles were included in the final analysis representing 21 African countries and 6,029 children with confirmed meningitis. In these studies, nearly one fifth of bacterial meningitis survivors experienced in-hospital sequelae (median = 18%, interquartile range (IQR) = 13% to 27%). About a quarter of children surviving pneumococcal meningitis and Haemophilus influenzae type b (Hib) meningitis had neuropsychological sequelae by the time of hospital discharge, a risk higher than in meningococcal meningitis cases (median = 7%). The highest in-hospital case fatality ratios observed were for pneumococcal meningitis (median = 35%) and Hib meningitis (median = 25%) compared to meningococcal meningitis (median = 4%). The 10 post-discharge studies of children surviving bacterial meningitis were of varying quality. In these studies, 10% of children followed-up post discharge died (range = 0% to 18%) and a quarter of survivors had neuropsychological sequelae (range = 3% to 47%) during an average follow-up period of 3 to 60 months.
Bacterial meningitis in Africa is associated with high mortality and risk of neuropsychological sequelae. Pneumococcal and Hib meningitis kill approximately one third of affected children and cause clinically evident sequelae in a quarter of survivors prior to hospital discharge. The three leading causes of bacterial meningitis are vaccine preventable, and routine use of conjugate vaccines could provide substantial health and economic benefits through the prevention of childhood meningitis cases, deaths and disability.
PMCID: PMC2759956  PMID: 19751516
20.  In-hospital management of children with bacterial meningitis in Italy 
Over the years 2009–2013, we conducted a prospective study within a network established by the Italian Society of Pediatrics to describe the in-hospital management of children hospitalized for acute bacterial meningitis in 19 Italian hospitals with pediatric wards.
Hospital adherence to the study was voluntary; data were derived from clinical records. Information included demographic data, dates of onset of first symptoms, hospitalization and discharge; diagnostic evaluation; etiology; antimicrobial treatment; treatment with dexamethasone; in-hospital complications; neurological sequelae and status at hospital discharge. Characteristics of in-hospital management of patients were described by causative agent.
Eighty-five patients were identified; 49.4% had received an antimicrobial treatment prior to admission. Forty percent of patients were transferred from other Centers; the indication to seek for hospital care was given by the primary care pediatrician in 80% of other children. Etiological agent was confirmed in 65.9% of cases; the most common infectious organism was Neisseria meningitidis (34.1%), followed by Streptococcus pneumoniae (20%). Patients with pneumococcal meningitis had a significant longer interval between onset of first symptoms and hospital admission. Median interval between the physician suspicion of meningitis and in-hospital first antimicrobial dose was 1 hour (interquartile range [IQR]: 1–2 hours). Corticosteroids were given to 63.5% of cases independently of etiology; 63.0% of treated patients received dexamethasone within 1 hour of antibiotic treatment, and 41.2% were treated for ≤4 days. Twenty-nine patients reported at least one in-hospital complication (34.1%). Six patients had neurological sequelae at discharge (7.1%). No deaths were observed.
We observed a rate of meningitis sequelae at discharge similar to that reported by other western countries. Timely assistance and early treatment could have contributed to the favorable outcome that was observed in the majority of cases. Adherence to recommendation for corticosteroid adjunctive therapy seems suboptimal, and should be investigated in further studies. Most meningitis cases were due to N. meningitidis and S. pneumoniae. Reaching and maintaining adequate vaccination coverage against pneumococcal and meningococcal invasive infections remains a priority to prevent bacterial meningitis cases.
PMCID: PMC4247725  PMID: 25584885
Bacterial meningitis; Children; Meningitis sequelae; Neisseria meningitidis; Streptococcus pneumoniae
21.  Clinical indicators of bacterial meningitis among neonates and young infants in rural Kenya 
BMC Infectious Diseases  2011;11:301.
Meningitis is notoriously difficult to diagnose in infancy because its clinical features are non-specific. World Health Organization (WHO) guidelines suggest several indicative signs, based on limited data. We aimed to identify indicators of bacterial meningitis in young infants in Kenya, and compared their performance to the WHO guidelines. We also examined the feasibility of developing a scoring system for meningitis.
We studied all admissions aged < 60 days to Kilifi District Hospital, 2001 through 2005. We evaluated clinical indicators against microbiological findings using likelihood ratios. We prospectively validated our findings 2006 through 2007.
We studied 2,411 and 1,512 young infants during the derivation and validation periods respectively. During derivation, 31/1,031 (3.0%) neonates aged < 7 days and 67/1,380 (4.8%) young infants aged 7-59 days (p < 0.001) had meningitis. 90% of cases could be diagnosed macroscopically (turbidity) or by microscopic leukocyte counting. Independent indicators of meningitis were: fever, convulsions, irritability, bulging fontanel and temperature ≥ 39°C. Areas under the receiver operating characteristic curve in the validation period were 0.62 [95%CI: 0.49-0.75] age < 7 days and 0.76 [95%CI: 0.68-0.85] thereafter (P = 0.07), and using the WHO signs, 0.50 [95%CI 0.35-0.65] age < 7 days and 0.82 [95%CI: 0.75-0.89] thereafter (P = 0.0001). The number needed to LP to identify one case was 21 [95%CI: 15-35] for our signs, and 28 [95%CI: 18-61] for WHO signs. With a scoring system, a cut-off of ≥ 1 sign offered the best compromise on sensitivity and specificity.
Simple clinical signs at admission identify two thirds of meningitis cases in neonates and young infants. Lumbar puncture is essential to diagnosis and avoidance of unnecessary treatment, and is worthwhile without CSF biochemistry or bacterial culture. The signs of Meningitis suggested by the WHO perform poorly in the first week of life. A scoring system for meningitis in this age group is not helpful.
PMCID: PMC3217941  PMID: 22044635
meningitis; "young infants"; neonates; "lumbar puncture"; "clinical signs"; "resource-poor"
22.  Serum Procalcitonin in Viral and Bacterial Meningitis 
In children with meningitis, there is a difficulty to verify the etiology as viral or bacterial. Therefore, intensive research has been carried out to find new and rapid diagnostic methods for differentiating bacterial from viral meningitis.
The aim of this work was to study the behavior of procalcitonin (PCT) and whether it can be used to differentiate children with bacterial from those with viral meningitis. We also compared PCT to C-reactive protein (CRP) and white blood cell count.
Patients and Methods:
Forty children aged from 4 months to 12 years with clinically suspected meningitis were studied. Lumbar punctures were done for all cases before starting initial antibiotic treatment. According to the results of bacterial cultures and cerebrospinal fluid (CSF) cytochemical profile, our patients were classified into two groups: bacterial meningitis group and viral meningitis group. PCT, CRP, and leukocyte count were measured at the time of admission and after 3 days.
Forty children aged from 4 months to 12 years with clinically suspected meningitis were studied. Lumbar punctures were done for all cases before starting initial antibiotic treatment. According to the results of bacterial cultures and cerebrospinal fluid (CSF) cytochemical profile, our patients were classified into two groups: bacterial meningitis group and viral meningitis group. PCT, CRP, and leukocyte count were measured at the time of admission and after 3 days.
PCT levels were significantly higher in patients with bacterial meningitis (mean, 24.8 ng/ml) compared to patients with viral meningitis (mean, 0.3 ng/ml) (P<0.001). PCT levels in bacterial meningitis group decreased after 3 days of starting treatment, but remained higher than viral meningitis group (mean, 10.5 ng/ml). All CSF parameters, blood leukocytes, and CRP showed overlapping values between the two groups. Serum PCT with cut off value >2 ng/ml showed sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 66%, 68%, and 100%, respectively, for the diagnosis of bacterial meningitis.
Serum procalcitonin level has a better diagnostic and prognostic value than CRP or leukocyte count to distinguish between bacterial and viral meningitis. It is also a good indicator of the efficacy of treatment of bacterial meningitis.
PMCID: PMC3068572  PMID: 21572603
C-reactive protein; Meningitis; Procalcitonin
23.  Bacterial meningitis--ten years experience. 
The Journal of Hygiene  1982;88(3):383-401.
Between January 1968 and December 1977, 635 cases of acute bacterial meningitis were admitted to hospitals in the Birmingham Area Health Authority. The epidemiology of these cases was analysed and compared with the 270 cases which were admitted to the regional infectious diseases unit at East Birmingham Hospital (E.B.H.). In children and young adults the meningococcus was the commonest causative organism while over the age of 25 pneumococcal meningitis predominated. Although Haemophilus influenzae was the second commonest infecting organism it was a rare cause of meningitis in school children and adults, only four cases presenting in these age groups in the Birmingham Area. A detailed analysis was made of the symptoms, signs, laboratory investigations and clinical course of the 270 cases treated at E.B.H. The mortality in the patients with pneumococcal meningitis was 30%. In the meningococcal group it was 3.5% and in the haemophilus groups 7.7%. An analysis of the various treatment regimes employed in the 270 E.B.H. patients supports the view that a single antibiotic is sufficient for the therapy of most forms of bacterial meningitis. Intrathecal antibiotic administration is unnecessary in pyogenic meningitis caused by meningococci, pneumococci or H. influenzae.
PMCID: PMC2134113  PMID: 7086113
24.  Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at:
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at:
For more information on the economic analysis, please visit the PATH website:
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website:
The objective of this analysis was to determine the effectiveness of the influenza vaccination and the pneumococcal vaccination in patients with chronic obstructive pulmonary disease (COPD) in reducing the incidence of influenza-related illness or pneumococcal pneumonia.
Clinical Need: Condition and Target Population
Influenza Disease
Influenza is a global threat. It is believed that the risk of a pandemic of influenza still exists. Three pandemics occurred in the 20th century which resulted in millions of deaths worldwide. The fourth pandemic of H1N1 influenza occurred in 2009 and affected countries in all continents.
Rates of serious illness due to influenza viruses are high among older people and patients with chronic conditions such as COPD. The influenza viruses spread from person to person through sneezing and coughing. Infected persons can transfer the virus even a day before their symptoms start. The incubation period is 1 to 4 days with a mean of 2 days. Symptoms of influenza infection include fever, shivering, dry cough, headache, runny or stuffy nose, muscle ache, and sore throat. Other symptoms such as nausea, vomiting, and diarrhea can occur.
Complications of influenza infection include viral pneumonia, secondary bacterial pneumonia, and other secondary bacterial infections such as bronchitis, sinusitis, and otitis media. In viral pneumonia, patients develop acute fever and dyspnea, and may further show signs and symptoms of hypoxia. The organisms involved in bacterial pneumonia are commonly identified as Staphylococcus aureus and Hemophilus influenza. The incidence of secondary bacterial pneumonia is most common in the elderly and those with underlying conditions such as congestive heart disease and chronic bronchitis.
Healthy people usually recover within one week but in very young or very old people and those with underlying medical conditions such as COPD, heart disease, diabetes, and cancer, influenza is associated with higher risks and may lead to hospitalization and in some cases death. The cause of hospitalization or death in many cases is viral pneumonia or secondary bacterial pneumonia. Influenza infection can lead to the exacerbation of COPD or an underlying heart disease.
Streptococcal Pneumonia
Streptococcus pneumoniae, also known as pneumococcus, is an encapsulated Gram-positive bacterium that often colonizes in the nasopharynx of healthy children and adults. Pneumococcus can be transmitted from person to person during close contact. The bacteria can cause illnesses such as otitis media and sinusitis, and may become more aggressive and affect other areas of the body such as the lungs, brain, joints, and blood stream. More severe infections caused by pneumococcus are pneumonia, bacterial sepsis, meningitis, peritonitis, arthritis, osteomyelitis, and in rare cases, endocarditis and pericarditis.
People with impaired immune systems are susceptible to pneumococcal infection. Young children, elderly people, patients with underlying medical conditions including chronic lung or heart disease, human immunodeficiency virus (HIV) infection, sickle cell disease, and people who have undergone a splenectomy are at a higher risk for acquiring pneumococcal pneumonia.
Influenza and Pneumococcal Vaccines
Trivalent Influenza Vaccines in Canada
In Canada, 5 trivalent influenza vaccines are currently authorized for use by injection. Four of these are formulated for intramuscular use and the fifth product (Intanza®) is formulated for intradermal use.
The 4 vaccines for intramuscular use are:
Fluviral (GlaxoSmithKline), split virus, inactivated vaccine, for use in adults and children ≥ 6 months;
Vaxigrip (Sanofi Pasteur), split virus inactivated vaccine, for use in adults and children ≥ 6 months;
Agriflu (Novartis), surface antigen inactivated vaccine, for use in adults and children ≥ 6 months; and
Influvac (Abbott), surface antigen inactivated vaccine, for use in persons ≥ 18 years of age.
FluMist is a live attenuated virus in the form of an intranasal spray for persons aged 2 to 59 years. Immunization with current available influenza vaccines is not recommended for infants less than 6 months of age.
Pneumococcal Vaccine
Pneumococcal polysaccharide vaccines were developed more than 50 years ago and have progressed from 2-valent vaccines to the current 23-valent vaccines to prevent diseases caused by 23 of the most common serotypes of S pneumoniae. Canada-wide estimates suggest that approximately 90% of cases of pneumococcal bacteremia and meningitis are caused by these 23 serotypes. Health Canada has issued licenses for 2 types of 23-valent vaccines to be injected intramuscularly or subcutaneously:
Pneumovax 23® (Merck & Co Inc. Whitehouse Station, NJ, USA), and
Pneumo 23® (Sanofi Pasteur SA, Lion, France) for persons 2 years of age and older.
Other types of pneumococcal vaccines licensed in Canada are for pediatric use. Pneumococcal polysaccharide vaccine is injected only once. A second dose is applied only in some conditions.
Research Questions
What is the effectiveness of the influenza vaccination and the pneumococcal vaccination compared with no vaccination in COPD patients?
What is the safety of these 2 vaccines in COPD patients?
What is the budget impact and cost-effectiveness of these 2 vaccines in COPD patients?
Research Methods
Literature search
Search Strategy
A literature search was performed on July 5, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2000 to July 5, 2010. The search was updated monthly through the AutoAlert function of the search up to January 31, 2011. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Data extraction was carried out by the author.
Inclusion Criteria
studies comparing clinical efficacy of the influenza vaccine or the pneumococcal vaccine with no vaccine or placebo;
randomized controlled trials published between January 1, 2000 and January 31, 2011;
studies including patients with COPD only;
studies investigating the efficacy of types of vaccines approved by Health Canada;
English language studies.
Exclusion Criteria
non-randomized controlled trials;
studies investigating vaccines for other diseases;
studies comparing different variations of vaccines;
studies in which patients received 2 or more types of vaccines;
studies comparing different routes of administering vaccines;
studies not reporting clinical efficacy of the vaccine or reporting immune response only;
studies investigating the efficacy of vaccines not approved by Health Canada.
Outcomes of Interest
Primary Outcomes
Influenza vaccination: Episodes of acute respiratory illness due to the influenza virus.
Pneumococcal vaccination: Time to the first episode of community-acquired pneumonia either due to pneumococcus or of unknown etiology.
Secondary Outcomes
rate of hospitalization and mechanical ventilation
mortality rate
adverse events
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses. The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Efficacy of the Influenza Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The influenza vaccination was associated with significantly fewer episodes of influenza-related acute respiratory illness (ARI). The incidence density of influenza-related ARI was:
All patients: vaccine group: (total of 4 cases) = 6.8 episodes per 100 person-years; placebo group: (total of 17 cases) = 28.1 episodes per 100 person-years, (relative risk [RR], 0.2; 95% confidence interval [CI], 0.06−0.70; P = 0.005).
Patients with severe airflow obstruction (forced expiratory volume in 1 second [FEV1] < 50% predicted): vaccine group: (total of 1 case) = 4.6 episodes per 100 person-years; placebo group: (total of 7 cases) = 31.2 episodes per 100 person-years, (RR, 0.1; 95% CI, 0.003−1.1; P = 0.04).
Patients with moderate airflow obstruction (FEV1 50%−69% predicted): vaccine group: (total of 2 cases) = 13.2 episodes per 100 person-years; placebo group: (total of 4 cases) = 23.8 episodes per 100 person-years, (RR, 0.5; 95% CI, 0.05−3.8; P = 0.5).
Patients with mild airflow obstruction (FEV1 ≥ 70% predicted): vaccine group: (total of 1 case) = 4.5 episodes per 100 person-years; placebo group: (total of 6 cases) = 28.2 episodes per 100 person-years, (RR, 0.2; 95% CI, 0.003−1.3; P = 0.06).
The Kaplan-Meier survival analysis showed a significant difference between the vaccinated group and the placebo group regarding the probability of not acquiring influenza-related ARI (log-rank test P value = 0.003). Overall, the vaccine effectiveness was 76%. For categories of mild, moderate, or severe COPD the vaccine effectiveness was 84%, 45%, and 85% respectively.
With respect to hospitalization, fewer patients in the vaccine group compared with the placebo group were hospitalized due to influenza-related ARIs, although these differences were not statistically significant. The incidence density of influenza-related ARIs that required hospitalization was 3.4 episodes per 100 person-years in the vaccine group and 8.3 episodes per 100 person-years in the placebo group (RR, 0.4; 95% CI, 0.04−2.5; P = 0.3; log-rank test P value = 0.2). Also, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD.
Fewer patients in the vaccine group compared with the placebo group required mechanical ventilation due to influenza-related ARIs. However, these differences were not statistically significant. The incidence density of influenza-related ARIs that required mechanical ventilation was 0 episodes per 100 person-years in the vaccine group and 5 episodes per 100 person-years in the placebo group (RR, 0.0; 95% CI, 0−2.5; P = 0.1; log-rank test P value = 0.4). In addition, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD. The effectiveness of the influenza vaccine in preventing influenza-related ARIs and influenza-related hospitalization was not related to age, sex, severity of COPD, smoking status, or comorbid diseases.
Overall, significantly more patients in the vaccine group than the placebo group experienced local adverse reactions (vaccine: 17 [27%], placebo: 4 [6%]; P = 0.002). Significantly more patients in the vaccine group than the placebo group experienced swelling (vaccine 4, placebo 0; P = 0.04) and itching (vaccine 4, placebo 0; P = 0.04). Systemic reactions included headache, myalgia, fever, and skin rash and there were no significant differences between the 2 groups for these reactions (vaccine: 47 [76%], placebo: 51 [81%], P = 0.5).
With respect to lung function, dyspneic symptoms, and exercise capacity, there were no significant differences between the 2 groups at 1 week and at 4 weeks in: FEV1, maximum inspiratory pressure at residual volume, oxygen saturation level of arterial blood, visual analogue scale for dyspneic symptoms, and the 6 Minute Walking Test for exercise capacity.
There was no significant difference between the 2 groups with regard to the probability of not acquiring total ARIs (influenza-related and/or non-influenza-related); (log-rank test P value = 0.6).
Summary of Efficacy of the Pneumococcal Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The Kaplan-Meier survival analysis showed no significant differences between the group receiving the penumoccocal vaccination and the control group for time to the first episode of community-acquired pneumonia due to pneumococcus or of unknown etiology (log-rank test 1.15; P = 0.28). Overall, vaccine efficacy was 24% (95% CI, −24 to 54; P = 0.33).
With respect to the incidence of pneumococcal pneumonia, the Kaplan-Meier survival analysis showed a significant difference between the 2 groups (vaccine: 0/298; control: 5/298; log-rank test 5.03; P = 0.03).
Hospital admission rates and median length of hospital stays were lower in the vaccine group, but the difference was not statistically significant. The mortality rate was not different between the 2 groups.
Subgroup Analysis
The Kaplan-Meier survival analysis showed significant differences between the vaccine and control groups for pneumonia due to pneumococcus and pneumonia of unknown etiology, and when data were analyzed according to subgroups of patients (age < 65 years, and severe airflow obstruction FEV1 < 40% predicted). The accumulated percentage of patients without pneumonia (due to pneumococcus and of unknown etiology) across time was significantly lower in the vaccine group than in the control group in patients younger than 65 years of age (log-rank test 6.68; P = 0.0097) and patients with a FEV1 less than 40% predicted (log-rank test 3.85; P = 0.0498).
Vaccine effectiveness was 76% (95% CI, 20−93; P = 0.01) for patients who were less than 65 years of age and −14% (95% CI, −107 to 38; P = 0.8) for those who were 65 years of age or older. Vaccine effectiveness for patients with a FEV1 less than 40% predicted and FEV1 greater than or equal to 40% predicted was 48% (95% CI, −7 to 80; P = 0.08) and −11% (95% CI, −132 to 47; P = 0.95), respectively. For patients who were less than 65 years of age (FEV1 < 40% predicted), vaccine effectiveness was 91% (95% CI, 35−99; P = 0.002).
Cox modelling showed that the effectiveness of the vaccine was dependent on the age of the patient. The vaccine was not effective in patients 65 years of age or older (hazard ratio, 1.53; 95% CI, 0.61−a2.17; P = 0.66) but it reduced the risk of acquiring pneumonia by 80% in patients less than 65 years of age (hazard ratio, 0.19; 95% CI, 0.06−0.66; P = 0.01).
No patients reported any local or systemic adverse reactions to the vaccine.
PMCID: PMC3384373  PMID: 23074431
25.  Diagnostic Accuracy of Contrast-Enhanced FLAIR Magnetic Resonance Imaging in Diagnosis of Meningitis Correlated with CSF Analysis 
ISRN Radiology  2014;2014:578986.
Purpose. To determine the diagnostic accuracy of contrast enhanced FLAIR sequence of MRI brain in the diagnosis of meningitis. Subjects and Methods. A prospective study of 57 patients with signs and symptoms of meningitis, referred to the radiology department for MRI examination. Out of these, there were 30 males and 27 females. They underwent MRI brain with contrast including postcontrast T1W and FLAIR sequences. Cerebrospinal fluid (CSF) analysis obtained by lumbar puncture after MRI was considered the “reference standard” against which MRI findings were compared. Results. Of 57 patients, 50 were diagnosed as having meningitis on subsequent CSF analysis. Out of these 50, 49 were positive on postcontrast FLAIR images and 34 were positive on postcontrast T1W images. One patient was labeled false positive as CSF analysis showed malignant cells (leptomeningeal carcinomatosis). In the diagnosis of meningitis, the sensitivity of postcontrast FLAIR sequence was 96% and specificity 85.71%, whereas the sensitivity of postcontrast T1W sequence was 68% and specificity 85.71%. Conclusion. Contrast-enhanced FLAIR sequence is more sensitive and specific than contrast-enhanced T1W sequence in the diagnosis of meningitis. It should be routinely used in suspected cases of meningitis.
PMCID: PMC4062848  PMID: 24977138

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